Magnetic resonance imaging (MRI) has provided dramatic new capabilities for diagnostic medicine. MRI enables the acquisition of high resolution three-dimensional images, aiding detection of a wide variety of physical abnormalities, and recent advances in dynamic MRI are providing real-time imaging. Over 30% of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the proton relaxation and hence image quality. Gadolinium complexes are most widely used, and these complexes currently are all based on a poly(amino-carboxylate) ligand scaffold . Although the use of contrast agents has become routine, agents in clinical use are sub optimal in several important areas. Current imaging agents show relaxivities of less than 5% of the theoretical maximum. This low performance means that grams of gadolinium must be administered for a full-body MRI scan. This low sensitivity also precludes targeted imaging. The large amounts of agent used are particularly problematic in light of the recent research suggesting that nephrogenic systemic fibrosis (NSF, alternately NFD) is caused by release of Gd from the contrast agent before it clears through the kidneys. Improving performance, and thereby reducing dosage, would significantly improve patient safety. This project has developed gadolinium complexes based on a hexadentate hydroxypyridonate ligand scaffold that are stable and have substantially higher relaxivity due to a higher number of coordinated water molecules (2-3) and a water exchange rate at least two orders of magnitude higher than commercial agents. Having developed the agents and demonstrated their thermodynamic stability, we intend to continue their development, to enable new kinds of MR imaging. Relaxivities of more than 300mM-1s-1 are the target, to be achieved through the development of macromolecular contrast agents that are also highly stable. The use of macromolecular conjugation to improve relaxivity increases the need for high contrast agent kinetic stability. While long renal clearance times of most macromolecules allows for greater flexibility in image acquisition time, Gd dissociation will become an issue even in patients with healthy kidneys. There is therefore a need for agents with extremely high kinetic stability. If these agents also have higher performance compared to current agents, much less Gd will be needed to obtain an image. This will also enable new types of imaging with MRI. Thus the goals of this project are to improve contrast agent performance--both to lower administered doses and to enable target-selective imaging-and to develop agents with extremely high kinetic stability, to ensure patient safety. PUBLIC HEALTH RELEVANCE: Magnetic resonance imaging (MRI) has provided dramatic new capabilities for diagnostic medicine, with over 30% of MRI scans now acquired using a contrast agent, usually containing gadolinium, which enhances image quality. However, due to the low performance of current agents, gram quantities of gadolinium have to be injected into a patient, which has recently led to Nephrogenic Systemic Fibrosis in patients with kidney disorders. In order to prevent this toxic side effect of MRI contrast agents, we propose to improve the performance of MRI contrast agents up to two orders of magnitude over current agents and maximize in vivo stability to ensure patient safety.